Control of Neutrophilic Inflammation in Intestinal Health and Disease

控制肠道健康和疾病中的中性粒细胞炎症

基本信息

批准号：
10263264
负责人：
Beth A McCormick
金额：
$ 59.9万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-01 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10263264
关键词：
ABCB1 gene ATP-Binding Cassette Transporters Acute Address Agonist Anti-Inflammatory Agents Apical Bacterial Infections Biological Biological Assay CNR2 gene CRISPR/Cas technology Cannabinoids Cell surface Cells Chemotactic Factors Clinical Colitis Disease Eicosanoids Ensure Enteral Epithelial Epithelial Cells Equilibrium Ethanolamines Event Family Goals Health Homeostasis Host Defense Human Immune Immunotherapeutic agent Inflammation Inflammatory Inflammatory Response Injury Intervention Intestinal Mucosa Intestines Invaded Investigational Therapies Knock-in Knock-out Knowledge Lead Mediating Microfluidic Microchips Modeling Molecular Mucositis Mucous Membrane Nature Neutrophil Infiltration Pathologic Pathway interactions Pharmacologic Actions Pilot Projects Play Process Protocols documentation Receptor Activation Regulation Regulatory Pathway Role Severities Signal Transduction Stimulus Sum Surface System Testing Therapeutic Intervention Time Work arm base efflux pump endocannabinoid signaling epithelial injury experimental study first responder follow-up genome editing healing immunoregulation in vivo Model inflammatory disease of the intestine insight intestinal epithelium member microorganism migration neutrophil novel novel therapeutic intervention positive allosteric modulator receptor receptor binding receptor function recruit response sensor

项目摘要

Summary: The main objective of this proposal is to understand how neutrophils migrate across the intestinal epithelia, toward the eventual goal of manipulating this process in pathologic conditions where it can become excessive as in the context of idiopathic inflammatory intestinal disease as well as enteric bacterial infection. In particular, occurrence and severity of colitis appears to be correlated with the extent of neutrophil transmigration across the colonic epithelium and recent studies have shown that neutrophil migration can incite the migration of other cells that mediate inflammation. Thus, neutrophil transepithelial migration and accumulation at mucosal surfaces is a hallmark of many inflammatory conditions, and this process correlates directly with clinical disease activity and epithelial injury. Currently, the mechanisms that define neutrophil-epithelial interactions during an inflammatory response are not completely understood. To fill this gap in knowledge, we have uniquely shown that secretion of the eicosanoid hepoxilin A3 (HxA3) through the apically expressed efflux pump known as MRP-2 establishes the chemotactic gradient across the intestinal epithelium that is required for neutrophils from the submucosal space to move into the colonic lumen at times of inflammation. Additionally, we identified the N-acyl ethanolamine (NAE) class of eCBs to function in suppressing neutrophil transepithelial migration, and that these molecules are secreted through the apical efflux pump known as P-glycoprotein (P-gp). We hypothesize that these pro- and anti-inflammatory pathways communicate to provide a responsive, integrated mechanism to control inflammation status and that these are dysregulated in disease settings. To test this central hypothesis, we aim to identify the HxA3 receptor(s) on the cell surface of neutrophils (Aim 1), determine the nature of NAE-type ECBs/P-gp and HxA3/MRP2 signaling (Aim 2), and to explore crosstalk points between these two pathways that drive the inflammatory function of neutrophils (Aim 3). Successful completion of these Aims will provide a consolidated picture of mechanisms controlling neutrophil transmigration across the intestinal epithelium that will lead to both novel biological principles and therapeutic intervention strategies.

概括：该提案的主要目的是了解中性粒细胞如何穿过肠道迁移上皮细胞，以达到在病理条件下操纵这一过程的最终目标在特发性炎症性肠道疾病以及肠道细菌感染。特别是，结肠炎的发生和严重程度似乎相关与中性粒细胞跨结肠上皮迁移的程度有关，最近的研究表明研究表明，中性粒细胞迁移可以刺激介导炎症的其他细胞的迁移。因此，中性粒细胞跨上皮迁移和在粘膜表面的积累是许多炎症状况，这个过程与临床疾病活动直接相关和上皮损伤。目前，定义中性粒细胞-上皮相互作用的机制炎症反应期间的机制尚不完全清楚。为了填补这一知识空白，我们独特地表明，类二十烷酸 hepoxilin A3 (HxA3) 通过顶端分泌被称为 MRP-2 的表达外排泵在整个细胞内建立趋化梯度肠上皮是中性粒细胞从粘膜下间隙移动到炎症时的结肠腔。此外，我们还发现了 N-酰基乙醇胺 (NAE) 一类 eCB 具有抑制中性粒细胞跨上皮迁移的功能，并且这些分子通过称为 P-糖蛋白 (P-gp) 的顶端流出泵分泌。我们假设这些促炎和抗炎途径相互沟通以提供控制炎症状态的反应性、综合机制，并且这些机制失调在疾病环境中。为了检验这一中心假设，我们的目标是识别 HxA3 受体中性粒细胞的细胞表面（目标 1），确定 NAE 型 ECBs/P-gp 和 HxA3/MRP2 的性质信号传导（目标 2），并探索这两条路径之间的串扰点，从而驱动中性粒细胞的炎症功能（目标 3）。成功完成这些目标将提供控制中性粒细胞跨肠道迁移机制的综合图上皮细胞将导致新的生物学原理和治疗干预策略。